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Abstract Background Osteogenesis imperfecta (OI) is a rare hereditary bone disease resulting from a defect in collagen synthesis or processing, leading to bone fragility, frequent fractures and skeletal deformities. OI is associated with increased respiratory morbidity and mortality, but the mechanisms of lung involvement are poorly understood, and there are no data on the natural history of lung function. We studied lung function over time in a cohort of adult OI patients at one center. Methods We used data from OI patients aged 15 and above followed up at the Lausanne university hospital between 2012 and 2023 with available pre-bronchodilator spirometry. Associations between spirometric measurements at first visit and clinical characteristics were studied through linear regression. Changes of spirometric variables over time were analysed through mixed linear regression. Models were adjusted for age, sex, height and OI type (Sillence classification). Results Among 46 subjects, 24% had impaired spirometry at baseline, with similar distribution between restrictive (8.7%), obstructive (8.7%) and mixed (6.5%) ventilatory patterns. At first visit, higher age was associated with lower FEV1 (β = −0.019 l, p = 0.014) and lower FEV1/FVC (β = −0.175%, p = 0.012). A history of asthma was associated with higher FEV1 (β = 0.636 l, p = 0.028) and FVC (β = 0.834 l, p = 0.010). At first visit, FEV1 (β = −0.750 l, p = 0.006) and FVC (β = −0.859 l, p = 0.004) was lower in individuals with OI Sillence types 3, 4 or 5 compared to type 1. Over a mean follow-up of 3.4 years, smokers had a greater decline of FEV1/FVC compared to non-smokers (β = −6.592%, p = 0.007). Individuals with a mutation in the gene COL1A2 had 740 ml lower FVC compared to those with a mutation in COL1A1 (p = 0.037). After adjustment for sex, age, height and OI type, FEV1 increased by 26 ml (95% CI 8; 45) or 1.28%pred (0.51; 2.05) and FVC increased by 25 ml (95% CI 8; 43) or 0.93%pred (0.31; 1.55) per year of follow-up. Conclusions An increase of FEV1 and FVC over time was observed in OI patients after adjustment for other variables, suggesting that the defective collagen synthesis may impact the pulmonary interstitium and lead to increased lung compliance and hyperinflation, in contrast to skeletal deformities, which reduce the thoracic volume. Lung function changes in OI thus result from the interplay of several mechanisms.

Abstract Background The R-Scale-PF was proposed to evaluate the health-related quality of life (HRQoL) in patients with idiopathic pulmonary fibrosis (IPF). We generated a German version of the R-Scale-PF (GR-Scale), representing the first translation of the questionnaire into another language and assessed HRQoL longitudinally in various interstitial lung diseases (ILDs) using the R-Scale-PF scoring system at a specialized ILD centre. Methods We have translated the questionnaire in accordance with the WHO translation guidelines and applied it to 80 ILD patients of our department, with follow-ups after 3–6 months, assessing its internal consistency, floor and ceiling effects, concurrent validity, known-groups validity, and its responsiveness to changes over time. Results At baseline, all 80 patients completed the GR-Scale. In 70 patients (87.5%), follow-up data could be obtained after 4.43 ± 1.2 months. The GR-Scale demonstrated acceptable internal consistency (Cronbach’s α 0.749) and slight floor effects. Concurrent validity analysis showed weak but significant correlations with forced vital capacity (FVC; r=-0.282 p = 0.011) and diffusion capacity for carbon monoxide (DLco; r=-0.254 p = 0.025). In the follow-up analysis, moderate correlations were found with FVC (r=-0.41 p

Abstract Background 3D reconstruction of Wilms’ tumor provides several advantages but are not systematically performed because manual segmentation is extremely time-consuming. The objective of our study was to develop an artificial intelligence tool to automate the segmentation of tumors and kidneys in children. Methods A manual segmentation was carried out by two experts on 14 CT scans. Then, the segmentation of Wilms’ tumor and neoplastic kidney was automatically performed using the CNN U-Net and the same CNN U-Net trained according to the OV2ASSION method. The time saving for the expert was estimated depending on the number of sections automatically segmented. Results When segmentations were performed manually by two experts, the inter-individual variability resulted in a Dice index of 0.95 for tumor and 0.87 for kidney. Fully automatic segmentation with the CNN U-Net yielded a poor Dice index of 0.69 for Wilms’ tumor and 0.27 for kidney. With the OV2ASSION method, the Dice index varied depending on the number of manually segmented sections. For the segmentation of the Wilms’ tumor and neoplastic kidney, it varied respectively from 0.97 to 0.94 for a gap of 1 (2 out of 3 sections performed manually) to 0.94 and 0.86 for a gap of 10 (1 section out of 6 performed manually). Conclusion Fully automated segmentation remains a challenge in the field of medical image processing. Although it is possible to use already developed neural networks, such as U-Net, we found that the results obtained were not satisfactory for segmentation of neoplastic kidneys or Wilms’ tumors in children. We developed an innovative CNN U-Net training method that makes it possible to segment the kidney and its tumor with the same precision as an expert while reducing their intervention time by 80%.

Introduction: Medicinal plants have experienced a resurgence in usage over recent decades. Indeed, they constitute a therapeutic resource for a considerable proportion of the world's population. Nevertheless, evaluating the safety of these plants remains a challenge in ensuring their secure utilisation. Aim: The aim of this study was to assess the safety, tolerability and sedative effect of Feretia apodanthera Methods: A lyophilised aqueous infusion of Feretia apodanthera was prepared from dried leaf powder. The Organisation for Economic Co-operation and Development (OECD) guidelines 423 and 407 were employed. The initial assessment of acute toxicity was conducted by administering a single dose of 2,000 mg kg-1 of lyophilisate to female rats, after which the animals were observed for a period of 14 days. In a subsequent series of experiments, the subacute toxicity of the lyophilisate was evaluated through daily administrations of doses of 250 mg kg-1, 500 mg kg-1 and 1,000 mg kg-1 to both male and female rats over a period of 28 days. Furthermore, the potential sedative effect of the lyophilisate was investigated in mice. Results: In both single administration and repeated administration over 28 days in rats, the lyophilisate of the aqueous infusion of Feretia apodanthera did not induce mortality or significant changes in weight progression, water and food consumption, relative organ weights, or biochemical and haematological parameters, compared to the controls. However, it potentiated diazepam-induced sleep in mice. This sedative effect appears to involve an interaction with GABAA receptors. Conclusion: Although the sedative effect should be taken into account during use, the aqueous leaf infusion of Feretia apodanthera appears to be relatively well tolerated in both single and repeated administrations.

Sports are characterized by unique rules, environments, and tasks, but also share fundamental similarities with each other sport. Such between-sports parallels can be vital for optimizing talent transfer processes. This study aimed to explore similarities between sports to provide an objective basis for clustering sports into families by means of machine learning. An online survey was conducted, garnering responses from 1,247 coaches across 36 countries and 34 sports. The survey gauged the importance (0 = not important 10 = important) of 18 characteristics related to the sport and the athlete performing in that sport. These traits formed the basis for the categorization of a sport by means of machine learning, particularly unsupervised clustering, and the LIME feature explainer. Analysis grouped 34 sports into five clusters based on shared features. A similarity matrix illustrated the degree of overlap among sports. The application of unsupervised clustering emphasized the lack of a single overarching attribute across sports, marking a shift away from traditional clustering approaches that rely on a limited set of characteristics for talent transfer. The results highlight the importance of identifying common sports for talent transfer, which could prove advantageous in guiding athletes towards new sporting directions.

Introdução: O Serviço de Controle de Infecção Hospitalar (SCIH) é responsável por executar ações visando prevenir infecções hospitalares (IRAS). Objetivo: Estimar a economia gerada com a redução de infecções cirúrgicas (ISC), especificamente em procedimentos ortopédicos, e responder à pergunta: “Quanto um hospital ganha com os investimentos feitos em SCIH?”. Método: Coorte de cirurgias ortopédicas realizadas entre janeiro de 2019 e setembro de 2023 (Artroplastia de joelho, Artroplastia de quadril, Redução aberta de fratura). Os impactos da ISC em pacientes submetidos a estes procedimentos, em termos de risco de óbito e tempo de internação, foram estimados com base em dados coletados entre 2019 e 2022. Já o custo de cada infecção foi obtido de trabalhos da literatura, variando de R$ 38.062 e R$ 68.495. Principais intervenções do SCIH, implementadas a partir de abril de 2022: ATB no cimento ortopédico; Swab de aureus para vigilância; antibióticos de espectro estendido (cefuroxima com gentamicina) para profilaxia para pacientes com maior risco de ISC pós-operatória; repique intraoperatório quando necessário; auditaria de procedimentos cirúrgicos utilizando a equipe de controle de prevenção de infecções; boas p´raticas em sala curúrgica. Resultados: Avaliados de janeiro de 2019 a dezembro de 2022, 4.258 pacientes foram submetidos a cirurgias ortopédicas: AQ (11%), AJ (9%), redução aberta de fratura (80%). Destes, 2.439 eram mulheres (57%), 1.819 homens (43%), idade média e mediana de 51 anos, dp de 21 anos. Mortalidade de 1,6%, e taxa de ISC 5,6%. A ISC elevou o risco de mortalidade em mais de duas vezes RR 2,5, valor de p 0,014. A ISC foi associada à hospitalização prolongada; o tempo médio de permanência duplicou com infecção (18,2 dias) em comparação com sem infecção (9 dias), valor de p: 0,001. Comparando os riscos de infecção de 2019-2022 (5,6%) com 2023 (1,4%) após o investimento em controle de infecção, demonstrou-se uma redução do risco. Risco relativo (0,25) valor de p < 0,001. Conclusão: As ISC em cirurgias ortopédicas representam riscos duplos, aumentando readmissões e prejudicando o desempenho hospitalar. Investir na redução de ISC melhora o cuidado ao paciente, a segurança e proporciona retornos financeiros significativos. Este estudo destaca o retorno sobre o investimento (ROI) da prevenção de infecções, especialmente direcionado às infecções cirúrgicas ortopédicas. Prevenir ISC pode resultar em economias mensais de R$142.706,10 a R$256.797,91.

Introdução: Iniciativas baseadas em valor estão se tornando cada vez mais importantes como modelos estratégicos de gestão em saúde. A redução das taxas de infecção associada à assistência à saúde (IRAS), especialmente nas infecções de sítio cirúrgico (ISCs), tem sido atribuída ao desenvolvimento de programas de prevenção de infecções (PPI). Objetivo: Avaliar custo/benefício de investimentos contínuos na prevenção de ISCs, estimando o impacto destas infecções na lucratividade hospitalar. Método: Estudo de coorte retrospectivo de centro único, conduzido entre janeiro de 2019 e setembro de 2023, envolvendo pacientes submetidos a artroplastia, cirurgias de intestino delgado, colecistectomia, herniorrafia e redução de fraturas abertas. A definição de ISC seguiu os critérios estabelecidos pelo CDC/ANVISA. O custo de cada infecção foi obtido na literatura. O estudo comparou a incidência de ISC entre 2019-2022 versus 2023. O hospital implementou um Escritório de Valor em Saúde em 2022 para acelerar a disseminação do atendimento em saúde baseado em valor, com foco no PPI, incluindo medidas para prevenir ISCs: máxima aderência à profilaxia antimicrobiana, feedback sobre a taxa de ISC para a equipe cirúrgica com análise de causa raiz, auditoria de procedimentos cirúrgicos, reforço das boas práticas na sala de cirurgia e melhoria do centro de materiais e esterilização. Resultados: Durante o período basal (Jan/2019 - Dez/2022), foram incluídos 9.235 pacientes, sendo 59% mulheres e uma idade média de 51 anos. 368 foram diagnosticados com ISC, com taxa de mortalidade de 1,4%. Quando ocorre uma ISC, o tempo de internação é significativamente maior (p = 0,001) e o risco de morte dobra (RR = 2,1; p = 0,033). Houve redução de 64% nas taxas de ISC, de 4% em 2019-2022 para 1,4% em 2023. Isso se traduz em 63 infecções prevenidas e 2 mortes a menos. O estudo atribui esse sucesso às medidas preventivas implementadas, pois não houve diferença significativa em termos de duração da cirurgia (p = 0,411) e idade dos pacientes em cada grupo (p = 0,843). Além disso, a redução na taxa de ISC levou a estadias hospitalares mais curtas e economia mensal entre R$ 260.800 e R$ 469.327. Conclusão: As ISCs não apenas contribuem para readmissões, mas também impactam no desempenho do hospital. Investir em intervenções destinadas a reduzir infecções é essencial para melhorar o cuidado e a segurança do paciente. Este estudo destaca o retorno financeiro significativo associado ao investimento na prevenção de infecções.

As doses de P a serem aplicadas na cultura do milho comumente são elevadas em decorrência do baixo aproveitamento do nutriente devido a sua adsorção ao solo. O objetivo deste trabalho foi avaliar o uso das bactérias solubilizadoras de fosfato Bacillus megaterium e Bacillus subtilis, e do fungo micorrízico Rhizophagus intraradices, bem como a interação entre eles, e a possibilidade de redução da adubação fosfatada na cultura do milho. O delineamento experimental foi em blocos casualizados, em um fatorial 4x3, sendo o fator A composto por diferentes microrganismos solubilizadores de P (micorrizas e BiomaPhos®) e o fator B composto por diferentes doses de P (100, 75 e 50% da dose recomendada). A redução das doses de P, sem o uso de inoculantes, resultou em menor área foliar e teor de clorofila, porém não foi observado efeito significativo na altura das plantas. Nos componentes de rendimento número de grãos por espiga, peso de mil grãos e produtividade, a inoculação compensou a redução das doses. A aplicação de 50% da dose de P juntamente com a inoculação das bactérias foi o tratamento com maior margem bruta, sendo viável para a redução da adubação mineral.

Introduction The main risk factors of necrotising enterocolitis (NEC) are prematurity and low birth weight. The aim of our study was to identify risk factors for NEC in patients with duct-dependent congenital heart disease (CHD).Study design Newborns with duct-dependent CHD and NEC were matched 1:1 to those without NEC. Matched criteria were gestational age, birth weight, antenatal versus postnatal diagnosis and type of CHD.Results Twenty-three infants were included in each group. In the NEC group, mortality, length of intensive care unit stay and length of hospital stay were significantly higher (p=0.035; p

This article seeks to show how some syntactical, grammatical or lexical salience strategies work to enable the speaker, in vaccine-hesitant or conspiracy theory contexts, to legitimize their discourses and strengthen their authority as a reliable speaker in order to maximize the audience’s agreement with the theory. We define salience as the result of focusing strategies which do not rely on notions of information packaging, but on the selection of an interlocutive relation that can be disruptive, polemical, or consensual, and which enable the construction of a prevailing point of view. In this regard, such strategies are used for their cognitive effects on the audience, which, for example, allow for the topicalisation and focusing of a presupposed or shared knowledge, or for their argumentative advantage, as they allow for the restriction of meaning and the imposition of the speaker’s interpretation of reality, or for the emphasis on the viewpoint’s validity, significance or reliability.

Background: GPs are particularly vulnerable to job burnout. Tailored prevention and intervention strategies are needed. Aim: To investigate organisational, interpersonal, and individual factors contributing to exhaustion and disengagement at work among GPs. Design & setting: We conducted a cross-sectional study in a sample of Belgian GPs. Method: A total of 358 doctors (73% females, 301 with complete data) completed an online anonymous questionnaire assessing job burnout, psychosocial characteristics of the work environment, perceived social support in the private domain, emotional competence, and self-compassion. Results: GPs reported moderate levels of exhaustion and disengagement. Regression models showed that included factors jointly explained 69% of the variance in exhaustion and 63% in disengagement. Exhaustion was significantly predicted by female sex (β effect size = −0.1), high perceived emotional demands (β = 0.19), as well as low self-compassion (β = −0.14) and low emotional competence (β = 0.09). Disengagement was significantly predicted by low seniority (β = −0.12) and limited opportunities for development (β = −0.16). Both exhaustion and disengagement were predicted by low perceived quality of work (β = −0.19 and −0.14, respectively), meaning of work (β = −0.17 and −0.31, respectively), and role clarity (β = 0.09 and 0.12, respectively), as well as high perceived work–life conflict (β = 0.46 and 0.21, respectively). Moreover, GPs working in a multidisciplinary group reported lower levels of exhaustion and disengagement than those working in a monodisciplinary group or a solo practice, and this difference was associated with factors such as work–life conflict. Conclusion: Organisational, interpersonal, and intrapersonal factors interact to predict a substantial part of burnout in general practice. The most significant risk factors were perceived work–life conflict and poor meaning of work. Policymakers should work to support more sustainable practices based on the specific needs and constraints reported by GPs.

Abstract Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

Introduction: Infectious diseases, particularly among pediatric populations, represent a significant global health problems. Rational antibiotic use is paramount for achieving optimal patient outcomes, but prescribing antibiotics in pediatric settings is a multifaceted task influenced by various factors, including prescriber's knowledge and experience. Aim: This study, conducted at Pediatric Department at Bouaké University Hospital (Côte d'Ivoire) (CHU), aimed to investigate the relationship between prescriber's experience and the appropriateness of antibiotic prescriptions for pediatric patients. Material and Methods: The academic study lasted from June 1, 2019, to July 31, 2019, within the pediatric department of the Bouaké University Hospital. It included all children age 0 to 15 years, who were receiving antibiotic therapy for at least 48 hours. Evaluation of antibiotic therapy relied on criteria from authoritative references in infectious diseases. Antibiotic therapy was deemed appropriate if it was clinically justified for treating the specific infectious disease. Prescribers' experience-related variables, including years in medical practice, specialization level, and other pertinent factors, were integrated into the analysis to gain insights into their influence on the appropriateness and compliance of antibiotic prescriptions. Data analysis was executed using EPI INFO 2007 version 7.1.3.3 software, employing statistical tests such as Pearson's chi-square and Fisher's exact test. Results: The study unveiled that the incidence of antibiotic prescription among hospitalized children over the two-month period was 31.28%. Most prescribers had approximately 2 years of experience, with an average overall experience of 3.25 years. Male prescribers slightly outnumbered their female counterparts, and specialist physicians constituted the majority of prescribers (70.94%). Compliance was markedly higher among older children (46.76%) in comparison to infants (2.34%). Beta-lactam antibiotics were the most frequently prescribed class, accounting for 62.72% of antibiotic prescriptions. Non-compliance, particularly concerning dosage, was prevalent, contributing to 33.05% of cases, with betalactams being a prominent contributor. Conclusion: Although the influence of prescriber experience on antibiotic appropriateness remained inconclusive, the significance of rational antibiotic use remains pivotal. These findings underscore the necessity for continual efforts to optimize antibiotic therapy in pediatric care, endorsing evidence-based prescribing practices to safeguard the efficacy of antibiotics for future generations.

Background: Abdominal radiographs remain useful in newborns. Given the high radiation sensitivity of this population, it is necessary to optimize acquisition techniques to minimize radiation exposure. Objective: Evaluate the effects of three additional filtrations on radiation dose and image quality in abdominal X-rays of newborns using an anthropomorphic phantom. Material and method: Abdominal radiographs of an anthropomorphic newborn phantom were performed using acquisition parameters ranging from 55 to 70 kV and from 0.4 to 2.5 mAs, without and with three different additional filtrations: 0.1 mm copper (Cu) + 1 mm aluminum (Al), 0.2 mm copper + 1 mm aluminum, and 2 mm aluminum. For each X-ray the dose area product (DAP) was measured, the signal-to-noise ratio (SNR) was calculated, and image quality (IQ) was evaluated by two blinded radiologists using the absolute visual grading analysis (VGA) method. Results: Adding an additional filtration resulted in a significant reduction in DAP, with a decrease of 42% using 2 mm Al filtration, 65% with 0.1 mm Cu + 1 mm Al filtration, and 78% with 0.2 mm Cu + 1 mm Al filtration (p < 0.01). The addition of 2 mm aluminum filtration does not significantly decrease the SNR (p = 0.31), CNR (p = 0.52) or the IQ (p = 0.12 and 0.401 for reader 1 and 2, respectively). However, adding copper-containing filtration leads to a significant decrease in, SNR, CNR and IQ. Conclusion: Adding a 2 mm Al additional filtration for abdominal radiographs in newborns can significantly reduce the radiation dose without causing a significant decrease in image quality.

Objective Delineate the scope of teleconsultation services that can be effectively performed to provide women with comprehensive gynaecological and obstetrical care.Design Based on the literature and experts’ insights, we identified a list of gynaecological and obstetrical care practices suitable for teleconsultation. A three-round Delphi consensus survey was then conducted online among a panel of French experts. Experts using a 9-point Likert scale assessed the relevance of each teleconsultation practice in four key domains: prevention, gynaecology and antenatal and postnatal care. Consensus was determined by applying a dual-criteria approach: the median score on a 9-point Likert scale and the percentage of votes either below 5 or 5 and higher.Setting The study was conducted at a national level in France and involved multiple healthcare centres and professionals from various geographical locations.Participants The panel comprised 22 French experts with 19 healthcare professionals, including 12 midwives, 3 obstetricians-gynaecologists, 4 general practitioners and 3 healthcare system users. Participants were selected to include diverse practice settings encompassing hospital and private practices in both rural and urban areas.Primary and secondary outcome measures The study’s primary outcome was the identification of gynaecological and obstetrical care practices suitable for teleconsultation. Secondary outcomes included the level of professional consensus on these practices.Results In total, 71 practices were included in the Delphi survey. The practices approved for teleconsultation were distributed as follows: 92% in prevention (n=12/13), 55% in gynaecology (n=18/33), 31% in prenatal care (n=5/16) and 12% in postnatal care (n=1/9). Lastly, 10 practices remained under discussion: 7 in gynaecology, 2 in prenatal care and 1 in postnatal care.Conclusions Our consensus survey highlights both the advantages and limitations of teleconsultations for women’s gynaecological and obstetrical care, emphasising the need for careful consideration and tailored implementation.

Abstract When used in real‐world conditions, substantial interindividual variations in direct oral anticoagulant (DOAC) plasma concentrations are observed for a given dose, leading to a risk of over‐ or under‐exposure and clinically significant adverse events. Physiologically‐based pharmacokinetic (PBPK) models could help physicians to tailor DOAC prescriptions in vulnerable patient populations, such as those in the hospital setting. The present study aims to validate prospectively PBPK models for rivaroxaban and apixaban in a large cohort of elderly, polymorbid, and hospitalized patients. In using a model of geriatric population integrating appropriate physiological parameters into models first optimized with healthy volunteer data, observed plasma concentration collected in hospitalized patients on apixaban (n = 100) and rivaroxaban (n = 100) were adequately predicted (ratio predicted/observed area under the concentration curve for a dosing interval [AUCtau] = 0.97 [0.96–0.99] geometric mean, 90% confidence interval, ratio predicted/observed AUCtau = 1.03 [1.02–1.05]) for apixaban and rivaroxaban, respectively. Validation of the present PBPK models for rivaroxaban and apixaban in in‐patients represent an additional step toward the feasibility of bedside use.

Abstract Background There is a growing need to improve robustness of fattening pigs, but this trait is difficult to phenotype. Our first objective was to develop a proxy for robustness of fattening pigs by modelling the longitudinal energy allocation coefficient to growth, with the resulting environmental variance of this allocation coefficient considered as a proxy for robustness. The second objective was to estimate its genetic parameters and correlations with traits under selection and with phenotypes that are routinely collected. In total, 5848 pigs from a Pietrain NN paternal line were tested at the AXIOM boar testing station (Azay-sur-Indre, France) from 2015 to 2022. This farm is equipped with an automatic feeding system that records individual weight and feed intake at each visit. We used a dynamic linear regression model to characterize the evolution of the allocation coefficient between the available cumulative net energy, which was estimated from feed intake, and cumulative weight gain during the fattening period. Longitudinal energy allocation coefficients were analysed using a two-step approach to estimate both the genetic variance of the coefficients and the genetic variance in their residual variance, which will be referred to as the log-transformed squared residual (LSR). Results The LSR trait, which could be interpreted as an indicator of the response of the animal to perturbations/stress, showed a low heritability (0.05 ± 0.01), a high favourable genetic correlation with average daily growth (− 0.71 ± 0.06), and unfavourable genetic correlations with feed conversion ratio (− 0.76 ± 0.06) and residual feed intake (− 0.83 ± 0.06). Segmentation of the population in four classes using estimated breeding values for LSR showed that animals with the lowest estimated breeding values were those with the worst values for phenotypic proxies of robustness, which were assessed using records routinely collected on farm. Conclusions Results of this study show that selection for robustness, based on estimated breeding values for environmental variance of the allocation coefficients to growth, can be considered in breeding programs for fattening pigs.

Abstract Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 Å overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P3 binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of a broad lipid specificity of ATP8B1 and adds phosphatidylinositol as a transport substrate for ATP8B1. We report a critical role of the sn-2 ester bond of glycerophospholipids in substrate recognition by ATP8B1 through conserved S403. These findings provide fundamental insights into ATP8B1 catalytic cycle and regulation, and substrate recognition in P4-ATPases.

Abstract Habitat suitability models infer the geographical distribution of species using occurrence data and environmental variables. While data on species presence are increasingly accessible, the difficulty of confirming real absences in the field often forces researchers to generate them in silico. To this aim, pseudo‐absences are commonly sampled randomly across the study area (i.e. the geographical space). However, this introduces sample location bias (i.e. the sampling is unbalanced towards the most frequent habitats occurring within the geographical space) and favours class overlap (i.e. overlap between environmental conditions associated with species presences and pseudo‐absences) in the training dataset. To mitigate this, we propose an alternative methodology (i.e. the uniform approach) that systematically samples pseudo‐absences within a portion of the environmental space delimited by a kernel‐based filter, which seeks to minimise the number of false absences included in the training dataset. We simulated 50 virtual species and modelled their distribution using training datasets assembled with the presence points of the virtual species and pseudo‐absences collected using the uniform approach and other approaches that randomly sample pseudo‐absences within the geographical space. We compared the predictive performance of habitat suitability models and evaluated the extent of sample location bias and class overlap associated with the different sampling strategies. Results indicated that the uniform approach: (i) effectively reduces sample location bias and class overlap; (ii) provides comparable predictive performance to sampling strategies carried out in the geographical space; and (iii) ensures gathering pseudo‐absences adequately representing the environmental conditions available across the study area. We developed a set of R functions in an accompanying R package called USE to disseminate the uniform approach.

Abstract This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real‐world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model‐based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two‐compartment model with first‐order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P‐glycoprotein phenotypic (P‐gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15–29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P‐gp. A high interindividual variability in apixaban PKs was observed in a real‐life setting, which was partially explained by renal function and by P‐gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at‐risk patients.

Background: Molecular tests for suspicious thyroid nodules decrease rates of unnecessary surgeries but are not widely used due to reimbursement issues. The aim of this study was to assess the rate of unnecessary surgery performed in real-life setting for Bethesda III, IV and V nodules in the absence of molecular testing. Method: This is a single-center retrospective study of consecutive patients undergoing fine needle aspiration cytology (FNAC) with rapid on-site evaluation between January 2017 and December 2021. Unnecessary surgery was defined as surgery performed because of Bethesda III, IV, or V results in the absence of local compressive symptoms with final benign pathology and as second surgery for completion thyroidectomy. Results: In the 862 patients (640 females, mean age: 54.2 years), 1010 nodules (median size: 24.4 mm) underwent 1189 FNAC. Nodules were EU-TIRADS 2, 3, 4, and 5 in 3%, 34%, 42%, and 22% of cases, respectively. FNAC was Bethesda I, II, III, IV, V, and VI in 8%, 48%, 17%, 17%, 3%, and 6%, respectively. Surgery was performed in 36% of Bethesda III nodules (benign on pathology: 81%), in 74% of Bethesda IV nodules (benign on pathology: 76%) and in 97% of Bethesda V nodules (benign on pathology: 21%). Surgery was considered unnecessary in 56%, 68%, and 21% of patients with Bethesda III, IV, and V nodules, respectively. Conclusion: In this real data cohort surgery was unnecessary in more than half of patients with Bethesda III and IV nodules and in 21% of patients with Be thesda V nodules.

Abstract Over recent decades, our understanding of climate change has accelerated greatly, but unfortunately, observable impacts have increased in tandem. Both mitigation and adaptation have not progressed at the level or scale warranted by our collective knowledge on climate change. More effective approaches to engage people on current and future anthropogenic climate change effects are urgently needed. Here, we show how species whose distributions are shifting in response to climate change, that is, ‘species‐on‐the‐move’, present an opportunity to engage people with climate change by linking to human values, and our deep connections with the places in which we live, in a locally relevant yet globally coherent narrative. Species‐on‐the‐move can impact ecosystem structure and function, food security, human health, livelihoods, culture and even the climate itself through feedback to the climate system, presenting a wide variety of potential pathways for people to understand that climate change affects them personally as individuals. Citizen science focussed on documenting changes in biodiversity is one approach to foster a deeper engagement on climate change. However, other possible avenues, which may offer potential to engage people currently unconnected with nature, include arts, games or collaborations with rural agriculture (e.g. new occurrences of pest species) or fisheries organisations (e.g. shifting stocks) or healthcare providers (e.g. changing distributions of disease vectors). Through the importance we place on the aspects of life impacted by the redistribution of species around us, species‐on‐the‐move offer emotional pathways to connect with people on the complex issue of climate change in profound ways that have the potential to engender interest and action on climate change. Read the free Plain Language Summary for this article on the Journal blog.

Extramammary Paget disease (EMPD) is an uncommon adenocarcinoma of apocrine gland-rich areas, presenting significant diagnostic challenges due to its nonspecific clinical appearance and frequent misidentification as benign, inflammatory skin conditions. Traditional diagnostic methods such as biopsy are invasive and uncomfortable, often required repeatedly due to high recurrence rates. Dermoscopy and non-invasive imaging techniques have been used but provide limited diagnostic accuracy due to their constraints in depth penetration and resolution. Recent advancements in imaging technologies, such as line-field confocal optical coherence tomography (LC-OCT), show promise in enhancing diagnostic precision while minimizing invasive procedures. LC-OCT merges high-resolution imaging with deep penetration capabilities, capturing detailed horizontal and vertical skin images akin to histopathology. This study evaluated the diagnostic performance of LC-OCT in detecting EMPD and its recurrence in 17 clinically suspicious anogenital regions, belonging to six patients. Data were collected prospectively at the patient’s bedside by an LC-OCT expert with poor training for EMPD, and, then, reviewed retrospectively by an independent LC-OCT expert with adequate training for EMPD and no concerns about time. The prospective examination yielded 64.7% accuracy (11 true results out of 17 total cases), 71.4% sensitivity (10 true positives out of 14 actual positives), and 33.3% specificity (1 true negative out of 3 actual negatives). The retrospective analysis achieved 94.1% accuracy (16 true results out of 17 total cases), 100% sensitivity (14 true positives out of 14 actual positives), and 66.7% specificity (2 true positives out of 3 actual positives), with the only false positive case being a difficult-to-diagnose concomitant presentation of a lichen sclerosus et atrophicus. Despite the need for specialized training, our results suggest that LC-OCT represents a valuable tool for accurately identifying EMPD and improving its management by reducing unnecessary biopsies. Further studies are needed to standardize its clinical application.

Background: The Perfect Care (PC) initiative engages, educates, and enrolls adult cardiac surgery patients into a transformational program that includes an app for appointment scheduling, tracking biometric data and patient-reported outcomes, audiovisual visits, and messaging, paired with a digital health kit (consisting of a fitness tracker, scale, and sphygmomanometer). PC aims to reduce postoperative length of stay (LOS) as well as 30-day readmission and mortality. Methods: This was a retrospective review of patients who underwent coronary artery bypass (CAB), valve, or combined CAB and valve procedures at either of the 2 participating hospitals between April 2018 and March 2022. Patients who participated in the PC quality improvement initiative were compared to propensity-matched controls (1:1 matching). The evaluation focused on postoperative LOS and a novel composite measure comprising 30-day readmission and mortality. Results: Remote monitoring (PC) was associated with a shorter postoperative LOS, lower combined rate of 30-day readmission and mortality, and less variation compared to matched non-PC controls. Conclusions: Integrated improvements in postoperative remote monitoring of adult cardiac surgery patients may reduce time in the hospital and post-acute care facilities. Future prioritized efforts include the development of additional, personalized biometric monitoring devices, use of biometric data to augment risk assessment, and investigation of the value of remote monitoring on various patient risk profiles to address potential disparities in care.

Abstract Biological invasions have increased significantly with the tremendous growth of international trade and transport. Hematophagous arthropods can be vectors of infectious and potentially lethal pathogens and parasites, thus constituting a growing threat to humans—especially when associated with biological invasions. Today, several major vector-borne diseases, currently described as emerging or re-emerging, are expanding in a world dominated by climate change, land-use change and intensive transportation of humans and goods. In this review, we retrace the historical trajectory of these invasions to better understand their ecological, physiological and genetic drivers and their impacts on ecosystems and human health. We also discuss arthropod management strategies to mitigate future risks by harnessing ecology, public health, economics and social-ethnological considerations. Trade and transport of goods and materials, including vertebrate introductions and worn tires, have historically been important introduction pathways for the most prominent invasive hematophagous arthropods, but sources and pathways are likely to diversify with future globalization. Burgeoning urbanization, climate change and the urban heat island effect are likely to interact to favor invasive hematophagous arthropods and the diseases they can vector. To mitigate future invasions of hematophagous arthropods and novel disease outbreaks, stronger preventative monitoring and transboundary surveillance measures are urgently required. Proactive approaches, such as the use of monitoring and increased engagement in citizen science, would reduce epidemiological and ecological risks and could save millions of lives and billions of dollars spent on arthropod control and disease management. Last, our capacities to manage invasive hematophagous arthropods in a sustainable way for worldwide ecosystems can be improved by promoting interactions among experts of the health sector, stakeholders in environmental issues and policymakers (e.g. the One Health approach) while considering wider social perceptions. Graphical abstract

Abstract Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe -/- mice as well as hematopoietic deletion in Ldlr -/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe -/- Rag2 -/- Card9 -/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Abstract Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.

Abstract Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1 E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase β1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1 subunit.

Abstract Background Among the most widely predicted climate change-related impacts to biodiversity are geographic range shifts, whereby species shift their spatial distribution to track their climate niches. A series of commonly articulated hypotheses have emerged in the scientific literature suggesting species are expected to shift their distributions to higher latitudes, greater elevations, and deeper depths in response to rising temperatures associated with climate change. Yet, many species are not demonstrating range shifts consistent with these expectations. Here, we evaluate the impact of anthropogenic climate change (specifically, changes in temperature and precipitation) on species’ ranges, and assess whether expected range shifts are supported by the body of empirical evidence. Methods We conducted a Systematic Review, searching online databases and search engines in English. Studies were screened in a two-stage process (title/abstract review, followed by full-text review) to evaluate whether they met a list of eligibility criteria. Data coding, extraction, and study validity assessment was completed by a team of trained reviewers and each entry was validated by at least one secondary reviewer. We used logistic regression models to assess whether the direction of shift supported common range-shift expectations (i.e., shifts to higher latitudes and elevations, and deeper depths). We also estimated the magnitude of shifts for the subset of available range-shift data expressed in distance per time (i.e., km/decade). We accounted for methodological attributes at the study level as potential sources of variation. This allowed us to answer two questions: (1) are most species shifting in the direction we expect (i.e., each observation is assessed as support/fail to support our expectation); and (2) what is the average speed of range shifts? Review findings We found that less than half of all range-shift observations (46.60%) documented shifts towards higher latitudes, higher elevations, and greater marine depths, demonstrating significant variation in the empirical evidence for general range shift expectations. For the subset of studies looking at range shift rates, we found that species demonstrated significant average shifts towards higher latitudes (average = 11.8 km/dec) and higher elevations (average = 9 m/dec), although we failed to find significant evidence for shifts to greater marine depths. We found that methodological factors in individual range-shift studies had a significant impact on the reported direction and magnitude of shifts. Finally, we identified important variation across dimensions of range shifts (e.g., greater support for latitude and elevation shifts than depth), parameters (e.g., leading edge shifts faster than trailing edge for latitude), and taxonomic groups (e.g., faster latitudinal shifts for insects than plants). Conclusions Despite growing evidence that species are shifting their ranges in response to climate change, substantial variation exists in the extent to which definitively empirical observations confirm these expectations. Even though on average, rates of shift show significant movement to higher elevations and latitudes for many taxa, most species are not shifting in expected directions. Variation across dimensions and parameters of range shifts, as well as differences across taxonomic groups and variation driven by methodological factors, should be considered when assessing overall confidence in range-shift hypotheses. In order for managers to effectively plan for species redistribution, we need to better account for and predict which species will shift and by how much. The dataset produced for this analysis can be used for future research to explore additional hypotheses to better understand species range shifts.

Objectives: Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. Methods: This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. Results: At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P

A healthy man in his 40s was referred to the Oral Surgery and Implantology Unit of Geneva University Hospital for diagnosis and management of facial swelling affecting the right side of his lower jaw. The patient’s history revealed that the patient had been hit by several punches to the face a few months earlier. To investigate the swelling, an intra-oral radiograph, an orthopantomographic radiograph, and computed tomography were performed, which revealed no fracture of the lower jaw but the presence of a partly impacted fractured wisdom tooth (third molar). This finding, together with the clinical status, indicated cellulitis most likely related to the presence of a fractured wisdom tooth. The decision was made to proceed with tooth extraction, and follow-up at 3 weeks showed good healing and complete resolution of facial swelling. This case highlights that odontogenic infection can also occur as a result of necrosis following the fracture of an impacted wisdom tooth.

The study was carried out in the region of Placas, Pará. Objective: identify the main causing agents of mastitis, as well as evaluating the resistance profile of the isolated agents against antimicrobials. Methods: Ten properties were evaluated, where 161 animals were submitted to the California Mastitis Test (CMT) for the diagnosis of subclinical mastitis, and milk samples were collected from positive animals and led for culture and antibiogram. Results: In total, 31.06% of the animals were positive for CMT. The main agents identified were Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus agalactiae and Streptococcus bovis. The antibiogram indicated resistance to Penicillin, Ceftazidime and Cephalothin. Conclusion: The properties surveyed showed a high rate of subclinical mastitis, regarding antimicrobial resistance, in general, all agents showed high resistance.

ABSTRACTPharmacological approaches aimed at increasing autophagic flux and genetically engineered mice with autophagy deficiency in the endothelium have demonstrated that autophagy exerts vessel protection against metabolic stresses and vascular aging. However, the identity of the specific cellular processes that autophagy controls in endothelial cells remained unclear. In this punctum, we discuss our recent findings on the multiple functions of autophagy in the endothelium. Particularly, we highlighted that autophagy controls flow-mediated vascular reactivity and remodeling. We have also focused on the role of autophagy machinery in regulating protein distribution within the cell and on the results demonstrating how autophagy modulates the cellular response to the microenvironment changes.Abbreviations: CXCL12: C-X-C motif chemokine ligand 12 EDN1: Endothelin 1 eNOS: endothelial Nitric Oxide Synthase FGF: Fibroblast Growth Factor NO: Nitric oxide VEGF: Vascular Endothelial Growth Factor VEGFR2: Vascular Endothelial Growth Factor Receptor 2

BackgroundThe clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection.ObjectiveTo study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19.MethodsOne hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome.ResultsAlthough the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14–8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19.ConclusionThese findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs.Clinical trial registrationhttps://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584.

ABSTRACT Penicillin-binding proteins (PBPs) are key to the assembly of peptidoglycan, the major component of the bacterial cell wall. Although several PBP-specific regulatory proteins have been identified in different species, little is known about how the activity of PBPs is controlled and coordinated during the cell cycle. In this study, we characterize the unknown function protein Spr1400 and demonstrate its regulatory function on two PBPs in Streptococcus pneumoniae. For that, we use a combination of technics ranging from bacterial genetics and protein biochemistry to microscopy imaging. First, we show that pneumococcal Spr1400 localizes late to the cell division septum. Furthermore, deletion of spr1400 results in wider cells. Using co-immunoprecipitation and bacterial two hybrid (B2H), we observe that Spr1400 interacts with two PBPs, the class A PBP PBP1a and the class B PBP PBP2b, which are required for cell elongation. Microscale thermophoresis combined with B2H further reveals that these interactions occur through their transmembrane domains. We also show that Spr1400 co-localizes with PBP1a and PBP2b throughout the cell cycle. Strikingly, deletion of spr1400 alters the dynamics of PBP1a and PBP2b. Indeed, the two PBPs persist longer at the division site and localize later at the division site of daughter cells. Collectively, these data demonstrate that Spr1400, thus named CopD for coordinator of PBP1a and 2b dynamics, is a spatio-temporal regulator of PBP1a and PBP2b required for pneumococcal morphogenesis. IMPORTANCE Penicillin-binding proteins (PBPs) are essential for proper bacterial cell division and morphogenesis. The genome of Streptococcus pneumoniae encodes for two class B PBPs (PBP2x and 2b), which are required for the assembly of the peptidoglycan framework and three class A PBPs (PBP1a, 1b and 2a), which remodel the peptidoglycan mesh during cell division. Therefore, their activities should be finely regulated in space and time to generate the pneumococcal ovoid cell shape. To date, two proteins, CozE and MacP, are known to regulate the function of PBP1a and PBP2a, respectively. In this study, we describe a novel regulator (CopD) that acts on both PBP1a and PBP2b. These findings provide valuable information for understanding bacterial cell division. Furthermore, knowing that ß-lactam antibiotic resistance often arises from PBP mutations, the characterization of such a regulator represents a promising opportunity to develop new strategies to resensitize resistant strains.

Abstract Most statistical models of microclimate focus on the difference or ‘offset’ between standardized air temperatures (macroclimate) and those of a specific habitat such as forest understorey, grassland or under a log. However, these offsets can fluctuate from positive to negative over a single day such that common practice consists in aggregating data into daily mean, minimum and maximum before modelling monthly offsets for each summary statistic. Here, we propose a more parsimonious and flexible approach relying on just two parameters: the slope and equilibrium. The slope captures the linear relationship between microclimate and macroclimate, while the equilibrium is the point at which microclimate equals macroclimate. Although applicable to other habitats, we demonstrate the relevance of our method by focusing on forest understoreys. We installed temperature sensors at 1‐m height inside forest stands and in nearby open grasslands equipped with standardized weather stations, across 13 sites in France spanning a wide climatic gradient. From a year of hourly temperatures and for each sensor, we established relationships between microclimate and macroclimate temperatures using two linear mixed‐effects models, during the leaf‐on (May–November) and leaf‐off period (December–April). We extracted the monthly equilibrium and slope for each sensor, and used another set of linear mixed‐effects models to investigate their main determinants. The slope was chiefly determined by stand structure variables interacting with the leaf‐on/leaf‐off period: stand type (conifer vs broadleaf); shade‐casting ability; stand age; dominant height; stem density; and cover of the upper and lower shrub layer. In contrast, forest structure had no explanatory power on the equilibrium. We found the equilibrium to be positively related to mean macroclimate temperature, interacting with the open/forest habitat. The method introduced here overcomes several shortcomings of modelling microclimate offsets. By demonstrating that the slope and equilibrium vary in predictable ways, we have established a general linkage between microclimate and macroclimate temperatures that can be applied to any location or time if we know the mean macroclimate temperature (equilibrium) and buffering or amplifying capacity of the habitat (slope). We also warn about methodological biases due to the reference used for macroclimate.

Abstract The Arctic is the region on Earth that is warming at the fastest rate. In addition to rising means of temperature-related variables, Arctic ecosystems are affected by increasingly frequent extreme weather events causing disturbance to Arctic ecosystems. Here, we introduce a new dataset of bioclimatic indices relevant for investigating the changes of Arctic terrestrial ecosystems. The dataset, called ARCLIM, consists of several climate and event-type indices for the northern high-latitude land areas > 45°N. The indices are calculated from the hourly ERA5-Land reanalysis data for 1950–2021 in a spatial grid of 0.1 degree (~9 km) resolution. The indices are provided in three subsets: (1) the annual values during 1950–2021; (2) the average conditions for the 1991–2020 climatology; and (3) temporal trends over 1951–2021. The 72-year time series of various climate and event-type indices draws a comprehensive picture of the occurrence and recurrence of extreme weather events and climate variability of the changing Arctic bioclimate.

Ungulate herbivory is an important driver of ecological change in forests. Here, the authors combine vegetation resurveys showing herbivory effects are highly dependent on soil eutrophication, promoting non-natives under high N-conditions, yet benefiting threatened species under low N-conditions.

Abstract Probiotic supplementation can help to mitigate the pathogenesis of irritable bowel syndrome (IBS) by reinforcing the intestinal barrier, and reducing both inflammation and proteolytic activity. Here, a combination of in vitro tests was performed on 33 Bifidobacterium strains as probiotic candidates for IBS. In addition to the classical tests performed, the detection of the serine protease inhibitor (serpin) enzyme capable of decreasing the high proteolytic activity found in IBS patients was included. Three serpin-positive strains were selected: Bifidobacterium breve CNCM I-5644, Bifidobacterium longum subsp. infantis CNCM I-5645 and B. longum CNCM I-5646 for their immunomodulation properties and protection of intestinal epithelial integrity in vitro. Furthermore, we found that B. breve CNCM I-5644 strain prevented intestinal hyperpermeability by upregulating Cingulin and Tight Junction Protein 1 mRNA levels and reducing pro-inflammatory markers. The ability of CNCM I-5644 strain to restore intestinal hyperpermeability (FITC-dextran) was shown in the murine model of low-grade inflammation induced by dinitrobenzene sulfonic acid (DNBS). This effect of this strain was corroborated in a second model of IBS, the neonatal maternal separation model in mice. Altogether, these data suggest that serpin-positive B. breve CNCM I-5644 may partially prevent disorders associated with increased barrier permeability such as IBS.

Abstract Background Perineuronal nets (PNNs) are specialized extracellular matrix structures mainly found around fast-spiking parvalbumin (FS-PV) interneurons. In the adult, their degradation alters FS-PV-driven functions, such as brain plasticity and memory, and altered PNN structures have been found in neurodevelopmental and central nervous system disorders such as Alzheimer’s disease, leading to interest in identifying targets able to modify or participate in PNN metabolism. The serine protease tissue-type plasminogen activator (tPA) plays multifaceted roles in brain pathophysiology. However, its cellular expression profile in the brain remains unclear and a possible role in matrix plasticity through PNN remodeling has never been investigated. Result By combining a GFP reporter approach, immunohistology, electrophysiology, and single-cell RT-PCR, we discovered that cortical FS-PV interneurons are a source of tPA in vivo. We found that mice specifically lacking tPA in FS-PV interneurons display denser PNNs in the somatosensory cortex, suggesting a role for tPA from FS-PV interneurons in PNN remodeling. In vitro analyses in primary cultures of mouse interneurons also showed that tPA converts plasminogen into active plasmin, which in turn, directly degrades aggrecan, a major structural chondroitin sulfate proteoglycan (CSPG) in PNNs. Conclusions We demonstrate that tPA released from FS-PV interneurons in the central nervous system reduces PNN density through CSPG degradation. The discovery of this tPA-dependent PNN remodeling opens interesting insights into the control of brain plasticity.

Abstract Purpose We evaluated the clinical significance of magnetic resonance imaging (MRI) findings and their prognostic value for initial hearing loss and recovery in patients with sudden sensorineural hearing loss (SSNHL). Materials and Methods This retrospective study included consecutive adult patients with unilateral SSNHL, contrast‐enhanced MRI and audiometric testing evaluated in our institution between 2005 and 2017. MRI reports, patient data, treatment, and audiometric tests were reviewed, with the relationship between MRI findings and hearing loss/recovery analyzed. Results Overall, 266 patients were included. Additional symptoms comprised tinnitus (114/266; 43%), vertigo (45/266; 17%), ear pain (26/266; 10%), and ear pressure (6/266; 2%). At least one cardiovascular risk factor (hypertension, diabetes, hypercholesterolemia, cardiopathy, and active smoking) existed in 167/266 (63%) patients. Corticosteroid treatment was followed by 198/266 (74%) patients while contraindications/refusal/compliance precluded treatment in 68/266(26%). Complete, partial or slight hearing recovery occurred in 167/266 (63%) patients. Three MRI patient groups were identified: a group with normal MRI examinations or incidentalomas (128/266; 48%), a group with peripheral auditory system (PAS) lesions (95/266; 36%), and a group with central nervous system (CNS) lesions (43/266; 16%). PAS lesions included lesions from the cochlea to the brain stem (e.g., schwannoma, meningioma, labyrinthitis, intracochlear hemorrhage, vestibulocochlear neuritis), whereas CNS lesions corresponded in 42/43(98%) of cases to leukoaraiosis and other vascular lesions (e.g., stroke, hemorrhage, aneurysm, venous sinus thrombosis, and cavernoma). Belonging to one of the three MRI groups did not influence the degree of initial hearing loss, affected frequencies or treatment, p > .05. Gender and cardiovascular risk factors did neither affect initial hearing loss nor recovery. However, age > 70 years negatively affected initial hearing loss in all frequencies, as well as recovery in all frequencies except 1000 Hz. Also, poor recovery of initial high‐frequency hearing loss (>1000 Hz) was significantly associated with CNS lesions. Conclusion Age > 70 years and CNS lesions depicted by MRI independently predicted poor auditory recovery, albeit in different frequencies. Lay Summary In patients with sudden hearing loss, older age (above 70 years) predicts poorer hearing recovery than in younger patients in most hearing frequencies. In addition, abnormalities of brain tissue revealed by MRI predict poorer hearing recovery at high frequencies. Level of Evidence Level III.

OBJECTIVES:. Clinical sepsis phenotypes may be defined by a wide range of characteristics such as site of infection, organ dysfunction patterns, laboratory values, and demographics. There is a paucity of literature regarding the impact of site of infection on the timing and pattern of clinical sepsis markers. This study hypothesizes that important phenotypic variation in clinical markers and outcomes of sepsis exists when stratified by infection site. DESIGN:. Retrospective cohort study. SETTING:. Five hospitals within the Wake Forest Health System from June 2019 to December 2019. PATIENTS:. Six thousand seven hundred fifty-three hospitalized adults with a discharge International Classification of Diseases, 10th Revision code for acute infection who met systemic inflammatory response syndrome (SIRS), quick Sepsis-related Organ Failure Assessment (qSOFA), or Sequential Organ Failure Assessment (SOFA) criteria during the index hospitalization. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The primary outcome of interest was a composite of 30-day mortality or shock. Infection site was determined by a two-reviewer process. Significant demographic, vital sign, and laboratory result differences were seen across all infection sites. For the composite outcome of shock or 30-day mortality, unknown or unspecified infections had the highest proportion (21.34%) and CNS infections had the lowest proportion (8.11%). Respiratory, vascular, and unknown or unspecified infection sites showed a significantly increased adjusted and unadjusted odds of the composite outcome as compared with the other infection sites except CNS. Hospital time prior to SIRS positivity was shortest in unknown or unspecified infections at a median of 0.88 hours (interquartile range [IQR], 0.22–5.05 hr), and hospital time prior to qSOFA and SOFA positivity was shortest in respiratory infections at a median of 54.83 hours (IQR, 9.55–104.67 hr) and 1.88 hours (IQR, 0.47–17.40 hr), respectively. CONCLUSIONS:. Phenotypic variation in illness severity and mortality exists when stratified by infection site. There is a significantly higher adjusted and unadjusted odds of the composite outcome of 30-day mortality or shock in respiratory, vascular, and unknown or unspecified infections as compared with other sites.

Cuticular hydrocarbons of some Dolichoderinae species from France and various places like Spain, North Africa, and Italy were studied. The Tapinoma nigerrimum group was particularly analyzed and replaced in the genus Tapinoma. All species were correctly discriminated and a new hydrocarbons profile was found in Spanish mountains in the T. nigerrimum group, which was provisionally named T. sp. Spain. We added numerous unknown spots for the distribution of these ants. We also tested aggression between some T. magnum colonies and it appeared that this species forms supercolonies like other invasive species, but does not form giant supercolonies like the Argentine ant

ABSTRACT Introduction: Homografts and bovine jugular vein are the most commonly used conduits for right ventricular outflow tract reconstruction at the time of primary repair of truncus arteriosus. Methods: We reviewed all truncus patients from 1990 to 2020 in two mid-volume centers. Inclusion criteria were primary repair, age under one year, and implantation of either homograft or bovine jugular vein. Kaplan-Meier analysis was used to estimate survival, freedom from reoperation on right ventricular outflow tract, and freedom from right ventricular outflow tract reoperation or catheter intervention. Results: Seventy-three patients met the inclusion criteria, homografts were implanted in 31, and bovine jugular vein in 42. There was no difference in preoperative characteristics between the two groups. There were 25/73 (34%) early postoperative deaths and no late deaths. Follow-up for survivals was 17.5 (interquartile range 13.5) years for homograft group, and 11.5 (interquartile range 8.5) years for bovine jugular vein group (P=0.002). Freedom from reoperation on right ventricular outflow tract at one, five, and 10 years in the homograft group were 100%, 83%, and 53%; and in bovine jugular vein group, it was 100%, 85%, and 50% (P=0.79). There was no difference in freedom from reoperation or catheter intervention (P=0.32). Conclusion: Bovine jugular vein was equivalent to homografts up to 10 years in terms of survival and freedom from right ventricular outflow tract reoperation or catheter intervention. The choice of either valved conduit did not influence the durability of the right ventricle-pulmonary artery conduit in truncus arteriosus.